Basic Study
Copyright ©The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Sep 7, 2020; 26(33): 4933-4944
Published online Sep 7, 2020. doi: 10.3748/wjg.v26.i33.4933
Tumor necrosis factor alpha receptor 1 deficiency in hepatocytes does not protect from non-alcoholic steatohepatitis, but attenuates insulin resistance in mice
Sena Bluemel, Yanhan Wang, Suhan Lee, Bernd Schnabl
Sena Bluemel, Yanhan Wang, Suhan Lee, Bernd Schnabl, Department of Medicine, University of California San Diego, La Jolla, CA 92093, United States
Sena Bluemel, Division of Gastroenterology and Hepatology, University Hospital Zurich, Zurich 8091, Switzerland
Yanhan Wang, Bernd Schnabl, Department of Medicine, VA San Diego Healthcare System, San Diego, CA 92161, United States
Author contributions: Bluemel S performed experiments and wrote the manuscript; Wang Y and Lee S assisted with experiments; Schnabl B supervised the study and edited the manuscript; All authors approved the final version of the manuscript.
Supported by the Swiss National Science Foundation, No. P2SKP3_158649, No. P3400PB_171581, and No. P3P3PB_171582 (to Bluemel S); NIH grants (in part), No. R01 AA24726, No. U01 AA026939, and services provided by P30 DK120515 (to Schnabl B).
Institutional animal care and use committee statement: All animal studies were reviewed and approved by the Institutional Animal Care and Use Committee of the University of California, San Diego (IACUC Protocol No. S09042).
Conflict-of-interest statement: Schnabl B has been consulting for Ferring Research Institute, HOST Therabiomics, Intercept Pharmaceuticals and Patara Pharmaceuticals. Schnabl B’s institution UC San Diego has received research support from Axial Biotherapeutics, BiomX, CymaBay Therapeutics, NGM Biopharmaceuticals, and Synlogic Operating Company.
Data sharing statement: No additional data are available.
ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Corresponding author: Bernd Schnabl, MD, Professor, Department of Medicine, University of California San Diego, Biomedical Research Facility 2 (BRF2), Room 4A22, 9500 Gilman Drive, MC0063, La Jolla, CA 92093, United States. beschnabl@ucsd.edu
Received: March 28, 2020
Peer-review started: March 28, 2020
First decision: May 21, 2020
Revised: July 21, 2020
Accepted: August 12, 2020
Article in press: August 12, 2020
Published online: September 7, 2020
Abstract
BACKGROUND

End-stage liver disease caused by non-alcoholic steatohepatitis (NASH) is the second leading indication for liver transplantation. To date, only moderately effective pharmacotherapies exist to treat NASH. Understanding the pathogenesis of NASH is therefore crucial for the development of new therapies. The inflammatory cytokine tumor necrosis factor alpha (TNF-α) is important for the progression of liver disease. TNF signaling via TNF receptor 1 (TNFR1) has been hypothesized to be important for the development of NASH and hepatocellular carcinoma in whole-body knockout animal models.

AIM

To investigate the role of TNFR1 signaling in hepatocytes for steatohepatitis development in a mouse model of diet-induced NASH.

METHODS

NASH was induced by a western-style fast-food diet in mice deficient for TNFR1 in hepatocytes (TNFR1ΔHEP) and their wild-type littermates (TNFR1fl/fl). Glucose tolerance was assessed after 18 wk and insulin resistance after 19 wk of feeding. After 20 wk mice were assessed for features of NASH and the metabolic syndrome such as liver weight, liver steatosis, liver fibrosis and markers of liver inflammation.

RESULTS

Obesity, liver injury, inflammation, steatosis and fibrosis was not different between TNFR1ΔHEP and TNFR1fl/fl mice. However, Tnfr1 deficiency in hepatocytes protected against glucose intolerance and insulin resistance.

CONCLUSION

Our results indicate that deficiency of TNFR1 signaling in hepatocytes does not protect from diet-induced NASH. However, improved insulin resistance in this model strengthens the role of the liver in glucose homeostasis.

Keywords: Tumor necrosis factor alpha receptor 1, Non-alcoholic steatohepatitis, Non-alcoholic fatty liver disease, Type 2 diabetes, Insulin resistance, Glucose intolerance

Core tip: We investigated the role of hepatocellular tumor necrosis factor receptor 1 (TNFR1) signaling in diet-induced non-alcoholic steatohepatitis in mice with a deficiency for TNFR1 solely in hepatocytes. In contrast to most whole-body knock-out models, diet-induced non-alcoholic steatohepatitis is not aggravated by hepatocellular TNFR1 deficiency in our study. However, insulin resistance was markedly improved, which strengthens the role of the liver in glucose homeostasis.